(a) Technical Field
The present invention relates to a 2-(substituted ethynyl)quinoline derivative having an mGluR5 antagonistic activity and pharmaceutically acceptable salts thereof. The compound of the present invention can be useful as a medicament for treating and preventing mGluR5 receptor-mediated diseases such as Alzheimer's disease, senile dementia, Parkinson's disease, L-DOPA-induced dyskinesia, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, anxiety disorder, depression, neuropathic pain, drug dependence, fragile X syndrome, autism, migraine and gastroesophageal reflux disease (GERD).
(b) Background Art
Glutamate is a most important neurotransmitter in the human body, and divided into two groups of ionotropic receptor (iGluRs) and metabotropic receptor (mGluRs). iGluR refers to a ligand-gated ion channel. In particular, it may be divided into (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), N-methyl-D-acpartic acid (NMDA), and Kainate depending on the type of receptor-ligand interactions. mGluR is one of G-protein coupled receptors (GPCR), which may be divided into Groups I, II and III depending on its physiological characteristics. Group I is composed of mGluR1 and mGluR5, acts as a postsynaptic receptor which is involved in the enhancement of neuronal excitation, and activates PLC (phospholipase C) through Gq protein. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8) belong to a pretsynaptic receptor, and inhibit the activity of an adeninyl cyclic enzyme system activated through Gi protein.
mGluR5 is predominantly expressed in the hippocampus and cerebral cortex, mainly distributed in the postsynaptic membrane of neurons, and functions to regulate synaptic plasticity. It has been found that mGluR5 is immediately correlated with nervous diseases including fragile X syndrome, pain and drug addict (Pain 2005, 114, 195; Neuropharmacology 1999, 38, 1493; Neuropharmacology 2001, 41, 1; Curr. Drug Abuse Rev. 2009, 2, 83). The mGluR5-related diseases can be exemplified by degenerative nervous diseases such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis; mental illnesses such as schizophrenia and anxiety; depression, pain and drug dependence (Expert Opin. Ther. Patents (2002), 12(12)).
There has been an extensive effort to develop an mGluR5 antagonist. As a result, it has been found that 2-methyl-6-(phenylethynyl)pyridine (MPEP) shows a selective activity as an mGluR5 negative allosteric modulator and is effective for pain, anxiety disorder or depression. However, its pharmacokinetic profile was found to be very poor in clinical trials (Curr Opin. Invest. Dr. 2001, 1, 355; Psychopharmacology 2005, 179, 218). Further, it has been reported that ADX10059 (Gut. 2009, 58, 1192), which is developed as an mGluR5 antagonist having an alkyne moiety, is effective for fragile X syndrome, gastroesophageal reflux disease (GERD) or migraine. Patients with fragile X syndrome suffer from cognitive disorder, autistic spectrum disorder, aggressiveness, attack, anxiety, compulsive behavior disorder, excessive tactile sensitivity, diarrhea and excessive sensory sensitivity. A selective mGluR5 antagonist can be effectively used for treating fragile X syndrome, depression, Parkinson's disease or L-DOPA-induced dyskinesia. Therefore, there is still a need to develop a novel mGluR5 antagonist with improved selective activity.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the invention and therefore it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.